US5948777A - Cannabinoid receptor agonists - Google Patents
Cannabinoid receptor agonists Download PDFInfo
- Publication number
- US5948777A US5948777A US09/051,828 US5182898A US5948777A US 5948777 A US5948777 A US 5948777A US 5182898 A US5182898 A US 5182898A US 5948777 A US5948777 A US 5948777A
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- Prior art keywords
- adamantyl
- pyrazole
- carboxamide
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- ethoxy
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/06—Antipsoriatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Definitions
- the present invention relates to novel pyrazole derivatives, pharmaceutical compositions containing these compounds and their use as cannabinoid peripheral receptor agonists.
- Cannabinoids are a specific class of psychoactive compounds present in Indian cannabis (Cannabis sativa), including about sixty different molecules, the most representative being cannabinol, cannabidiol and several isomers of tetrahydrocannabinol.
- Indian cannabis canbis sativa
- cannabinol cannabidiol
- isomers of tetrahydrocannabinol Knowledge of the therapeutic activity of cannabis dates back to the ancient dynasties of China, where, 5,000 years ago, cannabis was used for the treatment of asthma, migraine and some gynaecological disorders. These uses later became so established that, around 1850, cannabis extracts were included in the US Pharmacopaeia and remained there until 1947.
- Cannabinoids are known to cause different effects on various systems and/or organs, the most important being on the central nervous system and on the cardiovascular system. These effects include alterations in memory and cognition, euphoria, and sedation. Cannabinoids also increase heart rate and vary systemic arterial pressure. Peripheral effects, such as bronchial dilation, immunomodulation, and downregulation of inflammation have also been observed. The capability of cannabinoids to reduce intraocular pressure and to affect respiratory and endocrine systems is also well documented. See e.g. L. E. Hollister, Health Aspects of Cannabis, Pharmacological Reviews, Vol. 38, pp. 1-20, (1986). More recently, it was found that cannabinoids suppress the cellular and humoral immune responses and exhibit antiinflammatory properties. Wirth et al., Antiinflammatory Properties of Cannabichrome, Life Science, Vol. 26, pp. 1991-1995, (1980).
- the first cannabinoid receptor was found to be mainly localized in the brain, and, only to a lesser extent, in peripheral tissues. In view of its mRNA localization, it was designated the central receptor ("CB1"). See Matsuda et al., "Structure of a Cannabinoid Receptor and Functional Expression of the Cloned cDNA," Nature, Vol. 346, pp. 561-564 (1990.
- the second cannabinoid receptor (“CB2”) was localized primarily to the spleen with low expression in the CNS, and was postulated to modulate the non psychoactive effects of the cannabinoids. See Munro et el., "Molecular Characterization of a Peripheral Receptor for Cannabinoids," Nature, Vol. 365, pp. 61-65 (1993).
- CB2 The role of CB2 in immunomodulation, inflammation, osteoporosis, cardiovascular, renal and other disease conditions is currently under examination.
- cannabinoids act on receptors capable of modulating different functional effects, and in view of the low homology between CB2 and CB 1, the importance of developing a class of drugs selective for the CB2 receptor subtype is evident.
- the natural or synthetic cannabinoids currently available do not fulfill this function because they are active on both receptor subtypes.
- CB2 agonists offer a unique approach toward the pharmacotherapy of immune disorders, inflammation, osteoporosis, renal ischemia and other pathophysiological conditions.
- the present invention provides novel pyrazole derivatives represented by Formula (I) and pharmaceutical compositions containing these compounds, and their use as CB2 receptor agonists which are useful in the treatment of a variety of diseases including but not limited to immune disorder, inflammation, osteoporosis, psoriasis, eczema and renal ischemia.
- the present invention further comprises a method for activating CB2 receptors in an animal, including humans, which comprises administering to an animal in need thereof an effective amount of a compound of Formula (I).
- A is selected from the group consisting of 1-adamantyl, 2-adamantyl, 3-noradamantyl, and 1,1,3,3-tetramethylbutyl;
- R 2 is selected from the group consisting of 2-(4-morpholino)ethoxy, 2-(diallylamino)ethoxy, 2-, 3-, or 4-pyridylmethoxy, 2-(diethylamino)ethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy and 4-substituted benzyloxy; where the substituent is selected from the group consisting of hydrogen, fluoro, chloro, methoxy, methylthio, and nitro; and
- R 1 is selected from the group consisting of C 1-6 alkyl, 3- or 4-biphenyl, unsubstituted or substituted by halo, 1-naphthyl, benzyl, phenethyl, phenyl, monosubstituted phenyl, wherein the substituent is selected from the group consisting of hydrogen, C 1-4 alkyl, fluoro, chloro, bromo, methoxy, trifluoromethyl, and nitro, or disubstituted phenyl where the substituents are, independently, selected from the group consisting of fluoro, chloro, or methyl.
- salt complexes include hydrochloride, hydrobromide, citrate, tartrate, malate, maleate, lactate, fructose 1,6-diphosphate, phosphate, succinate, sulfate, aspartate, adipate, methanesulfonate, lauryl sulfate, diguaiacyl phosphate, diacetyl sulfate, glutamate, gluconate, and edetate.
- All alkyl and alkoxy groups may be straight or branched.
- the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
- allyl means --CH 2 ⁇ CH--CH 2 --.
- A is 1-adamantyl, 2-adamantyl, or 3-noradamantyl
- R 2 is selected from the group consisting of 2-(4-morpholino)ethoxy, 4-pyridylmethoxy, 1-methylpiperidinyl-2-methoxy, benzyloxy, and 4-fluoro-benzyloxy
- R 1 is phenyl, benzyl, or 4-monosubstituted phenyl wherein the substitutent is selected from the group consisting of C 1-4 alkyl, fluoro, chloro, methoxy, and trifluoromethyl.
- A is 1-adamantyl
- R 2 is selected from the group consisting of 2-(4-morpholino)ethoxy, 4-pyridylmethoxy, and 1-methylpiperidinyl-2-methoxy
- R 1 is phenyl, benzyl, or 4-monosubstituted phenyl wherein the substitutent is selected from the group consisting of C 1-4 alkyl, fluoro, chloro, and methoxy.
- R 2 is 2-(4-morpholino)ethoxy
- R 1 is phenyl; or 4-monosubstituted phenyl wherein the substituent is C 1-4 alkyl.
- Preferred compounds useful in the present invention are selected from the group consisting of:
- More preferred compounds useful in the present invention are selected from the group consisting of:
- the most preferred compound useful in the present invention is:
- the present invention provides compounds of Formula (I): ##STR2## which can be prepared by processes described in Schemes 1 and 2 below. ##STR3## a) HOBT, EDC, TEA, DMF, A-NH 2 .
- a) converting the pyrazole-5-carboxylic acid 1 to the pyrazole-5-carbonyl chloride 2 employing standard conditions (such as treating with thionyl chloride either neat or in the presence of an inert solvent, or with oxalyl chloride in a suitable solvent such as benzene in presence of a catalytic amount of N,N-dimethylformamide) followed by:
- Formula (I) compounds wherein R 1 is 3- or 4-biphenyl are prepared by a process which comprises: reacting the corresponding Formula (I) compound wherein R 1 is 3-Br or 4-Br respectively with phenyl boronic acid in a suitable solvent (eg toluene-ethanol-water, 1,2-dimethoxyethane-water, tetrahydrofuran-water, or N,N-dimethylformamide-water) in the presence of a base (eg sodium carbonate, sodium bicarbonate, potassium carbonate, triethylamine) with 3 to 5 mole percent of a palladium derivative (eg palladium acetate, tetrakis(triphenylphosphine)palladium, or palladium acetate in the presence of bis(diphenylphosphino)butane) at 25 to 100° C. for 5 to 24 h.
- a suitable solvent eg toluene-ethanol-water, 1,2-dimethoxyethan
- the pyrazole-5-carboxylic acids (1) can be prepared by a process which comprises:
- modulator means both antagonist and agonist.
- the present modulators are agonists.
- treatment includes, but is not limited to prevention, retardation and prophylaxis of the disease.
- the present compounds are useful for the treatment of diseases including but not limited to immunologically-mediated inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, eczema, multiple schlerosis, diabetes and thyroiditis.
- diseases including but not limited to immunologically-mediated inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis, eczema, multiple schlerosis, diabetes and thyroiditis.
- the present compounds modulate bone formation/resorption and are useful in the treatment of conditions including but not limited to ankylosing spondylitis, gout, arthritis associated with gout, osteoarthritis and osteoporosis.
- Compounds of Formula (I) and their pharmaceutically acceptable salts may be administered in a standard manner for the treatment of the indicated diseases, for example orally, parentarally, sub-lingually, dermally, transdermally, rectally, via inhalation or via buccal administration.
- Composition of Formula (I) and their pharmaceutically acceptable salts which are active when given orally can be formulated as syrups, tablets, capsules and lozenges.
- a syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
- a liquid carrier for example, ethanol, peanut oil. olive oil, glycerine or water with a flavoring or coloring agent.
- any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose.
- composition is in the form of a capsule
- any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell.
- composition is in the form of a soft gelatin shell capsule
- any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell.
- Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
- a parenterally acceptable oil for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.
- compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.
- a typical suppository formulation comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
- a binding and/or lubricating agent for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.
- Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.
- the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.
- Each dosage unit for oral administration contains suitably from 0.1 mg to 500 mg/Kg, and preferably from 1 mg to 100 mg/Kg, and each dosage unit for parenteral administration contains suitably from 0.1 mg to 100 mg/Kg, of a compound of Formula(I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- Each dosage unit for intranasal administration contains suitably 1-400 mg and preferably 10 to 200 mg per person.
- a topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I).
- the daily dosage regimen for oral administration is suitably about 0.01 mg/Kg to 40 mg/Kg, of a compound of Formula(I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- the daily dosage regimen for parenteral administration is suitably about 0.001 mg/Kg to 40 mg/Kg, of a compound of Formula (I) or a pharmaceutically acceptable salt thereof calculated as the free base.
- the daily dosage regimen for intranasal administration and oral inhalation is suitably about 10 to about 500 mg/person.
- the active ingredient may be administered from 1 to 6 times a day, sufficient to exhibit the desired activity.
- CB2 membranes are made from a polyclonal HEK 293 cell line stabily expressing the human CB2 receptor.
- the assay buffer comprises 50 mM Tris(pH7.4), 5 mM MgCl2, 2.5 mM EDTA and 5 mg/ml Bovine Serium Albumin Fraction V fatty acid-free(Cal Biochem). Unless otherwise noted, all chemicals are from Sigma. Tritiated 5-(1,1-dimethylheptyl)-2-(5-hydroxypropyl)cyclohexyl)-1 alpha, 2beta, 5 alpha)-phenol( 3 H!-CP55,940,103.4 Ci/mmol, 1 mCi/ml) is purchased from DuPont NEN. Test compounds are made by Medicinal Chemistry SmithKline Beecham Pharmacuticals and are dissolved in DMSO.
- the ligand binding mixture contains 1.3-1.8 nM 3 H!-CP55,940, 20 ug of CB2 membranes and 5 ul of each test compound in a total reaction volume of 150 ul of assay buffer.
- the final concentrations of compounds range from 1.00E-4 to 1.00E-10M; and the final DMSO concentration is 3.3%.
- the ligand binding mixtures are incubated in 96 deep well polypropylene microtiter plates for one hour at 30° C.
- Polyclonal HEK293 cells stabily expressing human CB2 receptor are maintained in EMEM media supplemented with Earl's salts, L-glutamine, 10% FBS, and 0.5 mg/ml G418 sulfate. 200 ⁇ L of cell suspension (25,000-50,000 cells/well) are added to a 96 well plate pre-treated with dilute Matrigel (Collaborative Biomedical Products: diluted 1/50 with PBS and treated for 1 hr at room temperature) and incubated at 37° C. for three days in a 5% CO 2 incubator.
- dilute Matrigel Collaborative Biomedical Products: diluted 1/50 with PBS and treated for 1 hr at room temperature
- cAMP assay buffer EMEM media supplemented with Earl's salts, L-glutamine, 20 mM Hepes, pH 7.4, 0.1 mM MgCl 2 and 2 mg/ml BSA Fraction V
- 50 ⁇ L of assay buffer are added to each well, followed by 100 ⁇ L of 250 uM Zardaverine (a PDE 3-4 inhibitor diluted in assay buffer with 0.25% DMSO) and 50 ⁇ L of the test compound (diluted in assay buffer containing 20 mg/ml BSA and 1% DMSO). The cells are then incubated with compounds at room temperature for 30 minutes.
- Forskolin (Calbiochem 344270 in assay buffer with 0.1% DMSO) is added and incubated for 15 minutes in a 37° C. incubator. The reaction is terminated by addition of 60 uL 0.2N HCl and 0.2 mM CaCl 2 and stored in a -80 ° C. freezer until cAMP determination.
- cAMP determinations 200 ⁇ L of cell lysate is transferred to a 96 well round-bottom plate and 40 ⁇ L of 0.1N NaOH and 0.1 mM CaCl2 is added to neutralize the lysate. Following centrifugation at 2400 rpm for 5 minutes, 20-50 ⁇ L of supernatant is assayed for cAMP using the Amersham EIA kit (RPN 225: unacetylated protocol). Using this procedure, forskolin stimulated cAMP levels range from 0.5-1.5 pmole per assay well and 5-15 pmole per original culture.
- Formulations for pharmaceutical use incorporating compounds of the present invention can be prepared in various forms and with numerous excipients. Examples of such formulations are given below.
- a compound of Formula (I), (1 mg to 100 mg) is aerosolized from a metered dose inhaler to deliver the desired amount of drug per use.
- Ingredients 1, 2, 3 and 4 are blended in a suitable mixer/blender. Sufficient water is added portion-wise to the blend with careful mixing after each addition until the mass is of a consistency to permit its conversion to wet granules.
- the wet mass is converted to granules by passing it through an oscillating granulator using a No. 8 mesh (2.38 mm) screen.
- the wet granules are then dried in an oven at 140° F. (60° C.) until dry.
- the dry granules are lubricated with ingredient No. 5, and the lubricated granules are compressed on a suitable tablet press.
- a pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of formula I in polyethylene glycol with heating. This solution is then diluted with water for injections Ph Eur. (to 100 ml). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.
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- Physical Education & Sports Medicine (AREA)
- Diabetes (AREA)
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- Orthopedic Medicine & Surgery (AREA)
- Pain & Pain Management (AREA)
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Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/051,828 US5948777A (en) | 1997-03-18 | 1998-03-18 | Cannabinoid receptor agonists |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US4080897P | 1997-03-18 | 1997-03-18 | |
US4306097P | 1997-04-04 | 1997-04-04 | |
PCT/US1998/005352 WO1998041519A1 (fr) | 1997-03-18 | 1998-03-18 | Nouveaux agonistes de recepteurs de cannabinoides |
US09/051,828 US5948777A (en) | 1997-03-18 | 1998-03-18 | Cannabinoid receptor agonists |
Publications (1)
Publication Number | Publication Date |
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US5948777A true US5948777A (en) | 1999-09-07 |
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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US09/051,828 Expired - Fee Related US5948777A (en) | 1997-03-18 | 1998-03-18 | Cannabinoid receptor agonists |
Country Status (5)
Country | Link |
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US (1) | US5948777A (fr) |
EP (1) | EP0979228A4 (fr) |
JP (1) | JP2001516361A (fr) |
CA (1) | CA2283797A1 (fr) |
WO (1) | WO1998041519A1 (fr) |
Cited By (55)
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US6100259A (en) * | 1997-01-21 | 2000-08-08 | Smithkline Beecham Corporation | Cannabinoid receptor modulators |
WO2001028497A2 (fr) * | 1999-10-18 | 2001-04-26 | University Of Connecticut | Nouveaux agonistes de cannabinoides bicycliques destines au recepteur de cannabinoides |
US6274635B1 (en) | 1999-03-22 | 2001-08-14 | Immugen Pharmaceuticals Inc. | Alkylated resorcinol derivatives for the treatment of immune diseases |
WO2001074997A2 (fr) * | 2000-03-15 | 2001-10-11 | Shanghai Biowindow Gene Development Inc. | Nouveau polypeptide, proteine humaine de reception cannabinoide 11, et polynucleotide codant pour ce polypeptide |
US6479074B2 (en) | 1996-10-24 | 2002-11-12 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
US6566560B2 (en) | 1999-03-22 | 2003-05-20 | Immugen Pharmaceuticals, Inc. | Resorcinolic compounds |
US20030096844A1 (en) * | 2001-02-08 | 2003-05-22 | Schering Corporation | Cannabinoid receptor ligands |
WO2003042174A1 (fr) | 2001-11-14 | 2003-05-22 | Schering Corporation | Ligands du recepteur des cannabinoides |
US6572880B2 (en) | 1996-10-24 | 2003-06-03 | Pharmaceutical Applications Associates Llc | Methods and transdermal compositions for pain relief |
US20030120094A1 (en) * | 1998-05-04 | 2003-06-26 | Alexandros Makriyannis | Novel analgesic and immunomodulatory cannabinoids |
US20030149082A1 (en) * | 1998-06-09 | 2003-08-07 | Alexandros Makriyannis | Inhibitors of the anandamide transporter as analgesic agents |
US20030232859A1 (en) * | 2001-02-08 | 2003-12-18 | Schering Corporation | Cannabinoid receptor ligands |
US20030232101A1 (en) * | 2002-03-18 | 2003-12-18 | Immugen Pharmaceuticals, Inc. | Topical formulations of resorcinols and cannibinoids and methods of use |
US20040077649A1 (en) * | 2001-01-26 | 2004-04-22 | Alexandros Makriyannis | Novel cannabimimetic ligands |
US20040138315A1 (en) * | 2000-09-28 | 2004-07-15 | Immugen Pharmaceuticals, Inc. | Methods and compounds for inhibiting eicosanoid metabolism and platelet aggregation |
WO2004058251A1 (fr) * | 2002-12-19 | 2004-07-15 | University Of Massachusetts | Analogues de cannabinoides utiles comme activateurs gamma du recepteur nucleaire active par un proliferateur de peroxysome |
US20040186148A1 (en) * | 2003-03-20 | 2004-09-23 | Schering Corporation | Cannabinoid receptor ligands |
US20040192667A1 (en) * | 2001-08-31 | 2004-09-30 | University Of Connecticut | Novel pyrazole analogs acting on cannabinoid receptors |
US20040236101A1 (en) * | 2001-10-26 | 2004-11-25 | Alexandros Makriyannis | Heteroindanes a new class of potent cannabimimetic ligands |
US20040236116A1 (en) * | 2001-07-13 | 2004-11-25 | Alexandros Makriyannis | Novel bicyclic and tricyclic cannabinoids |
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US20040242593A1 (en) * | 2003-05-20 | 2004-12-02 | Moore Bob M. | Cannabinoid derivatives, methods of making, and use thereof |
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US6995187B1 (en) | 1999-10-18 | 2006-02-07 | University Of Connecticut | Peripheral cannabinoid receptor (CB2) selective ligands |
US20060030563A1 (en) * | 1999-10-18 | 2006-02-09 | Alexandros Makriyannis | Novel pyrazole analogs acting on cannabinoid receptors |
US20060100228A1 (en) * | 2004-06-22 | 2006-05-11 | Schering Corporation | Cannabinoid receptor ligands |
US20060189610A1 (en) * | 1999-10-18 | 2006-08-24 | Alexandros Makriyannis | Peripheral cannabinoid receptor (CB2) selective ligands |
US20060281738A1 (en) * | 2003-08-26 | 2006-12-14 | Hiroyuki Kai | 2-Naphthylimino-1,3-thiazine derivative |
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US7173027B2 (en) | 2001-01-29 | 2007-02-06 | University Of Connecticut | Receptor selective cannabimimetic aminoalkylindoles |
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US7253189B2 (en) | 2002-11-25 | 2007-08-07 | Schering Corporation | Cannabinoid receptor ligands |
US20070225280A1 (en) * | 2006-03-22 | 2007-09-27 | Kevin William Anderson | Adamantyl-pyrazole carboxamides as inhibitors of 11B-hydroxysteroid dehydrogenase |
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US20080125416A1 (en) * | 2004-08-27 | 2008-05-29 | Christian Laggner | Sigma Receptor Inhibitors |
US20080255224A1 (en) * | 2007-04-16 | 2008-10-16 | Blum Richard S | Pharmacological treatment of psoriasis |
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Also Published As
Publication number | Publication date |
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JP2001516361A (ja) | 2001-09-25 |
EP0979228A1 (fr) | 2000-02-16 |
WO1998041519A1 (fr) | 1998-09-24 |
EP0979228A4 (fr) | 2000-05-03 |
CA2283797A1 (fr) | 1998-09-24 |
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